POSTTRANSCRIPTIONAL REGULATION OF TRANSFORMING GROWTH FACTOR-BETA 1

在许多细胞类型中，测量到的 转化生长因子-β1(TGF-β1)mRNA和蛋白水平。 这表明翻译或翻译后机制发挥了作用。 在调节转化生长因子-β1的产生中起重要作用。临床上 类固醇激素超家族中的重要成员对这两个方面都有影响 流程。我们在转化生长因子中发现了一个新的上游起始位点- 并研究了起始部位的使用对 通过产生结构来调节信使核糖核酸 5‘和3’UR的不同部分已被删除。从 体外翻译实验结果显示，顺式基因的大体图谱-- 调节翻译效率的作用要素一直是 建造的。3‘UTR始终如一地刺激翻译，而 5‘端非编码区既含有刺激因子，又含有抑制因子。精选 可选择的转录起始点决定了这些中的哪些 元素占主导地位，并允许转化生长因子-β1的翻译效率 信使核糖核酸在16倍范围内变化。已经为以下方面开发了方法 人血浆中转化生长因子-β的准确测定。这个 抗雌激素，他莫昔芬，增加肿瘤中转化生长因子-β1的水平 乳腺癌患者的间质对循环中的转化生长因子没有影响。 Beta1水平。对类固醇和类固醇 相关化合物调节转化生长因子-β的产生和活性 生长抑制剂家族可能允许合理设计更有效的 用于化学预防或化疗的药理药剂 癌症。

In many cell types there is a large discrepancy between the measured levels of transforming growth factor-beta (TGF-beta1) mRNA and protein. This suggests that translational or post-translational mechanisms play an important role in the regulation of TGF-beta1 production. Clinically important members of the steroid hormone superfamily affect both these processes. We have identified a novel upstream start site in the TGF- beta1 MRNA, and have investigated the effects of start site usage on translational regulation of the MRNA by generating constructs in which various portions of the 5' and 3' UTRs have been deleted. From the results of in vitro translation experiments, a gross map of the cis- acting elements that regulate the translational efficiency has been constructed. The 3' UTR consistently stimulates translation, while the 5' UTR contains both stimulatory and inhibitory elements. Selection of alternative transcriptional start sites determines which of these elements dominates, and allows translational efficiency of the TGF-beta1 MRNA to vary over a 16-fold range. Methodology has been developed for accurate measurement of TGF-betas in the plasma of human subjects. The antiestrogen, tamoxifen, which increases TGF-beta1 levels in the tumor stroma of women with breast cancer, has no effect on circulating TGF- beta1 levels. An understanding of the mechanisms whereby steroids and related compounds regulate the production and activity of the TGF-beta family of growth inhibitors may allow the rational design of more potent pharmacological agents for use in chemoprevention or chemotherapy of cancer.